Previous opioid receptor binding studies of the locus coeruleus and electrophysiological studies of spinal cord reflexes have shown that the addition of large hydrophobic substituents to 7(-aminomethyl-8,14- endo-ethenotetrahydrooripavine produced amphiphiles, that were both potent and persistent opioid receptor agonists. These long-term effects may be due to accumulation and orientation of these compounds in the outer monolayer of neuronal membranes in a manner similar to native phospholipid components: the alkaloid portion at the surface and the hydrophobic N-acyl groups oriented toward the interior. To further test this hypothesis, the locus coeruleus slice preparation was used because it allows recording from isolated neurons that contain a preponderance of ( opioid receptors. We found that following very brief applications of small concentrations the hydrophobic compounds, a profound and long-lasting depression of neuronal firing in locus coeruleus occurred. Less hydrophobic congeners were much weaker in potentcy, and their action was rapidly reversed by their washout. Bath application of naloxone and its subsequent washout will demonstrate the persistent potency of the compounds with added hydrophobic substituents. Hydrophobicity studies, such as these, can lead to a better understanding of the role of the milieu of the opioid receptor transmembrane segments with respect to determining opioid potency and duration of action. Further, this understanding could lead to effective treatments for drug abuse.